What is the pathophysiology of simultaneous pancreas-kidney transplantation (SPKT)?related osteoporosis?

Updated: Jul 02, 2020
  • Author: Carmel M Fratianni, MD, FACE; Chief Editor: George T Griffing, MD  more...
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Answer

Simultaneous pancreas-kidney transplantation (SPKT) successfully restores euglycemia and insulin independence while reversing uremia in patients with ESRD due to diabetic nephropathy. While diabetic patients constitute approximately 20% of those receiving renal transplants, virtually all patients receiving both a pancreatic and renal transplant have type 1 diabetes mellitus. Because type 1 diabetes mellitus itself predisposes to cortical osteopenia and low bone turnover, patients with the condition are clearly at greater risk of transplant-associated bone disease and fracture. [54] The reasons for this are likely multifactorial.

Most patients with type 1 diabetes mellitus have not yet achieved peak bone mass before the onset of diabetes, and long-standing insulin deficiency may compromise bone mass. Multiple studies have documented that patients with type 1 diabetes have reduced BMD at all sites measured, with a high prevalence of osteoporosis. Munoz-Torres et al examined a cohort of 94 consecutive Spanish patients (aged 20-56 y) with type 1 diabetes of 1-35 years' duration presenting to a diabetes clinic for therapy and observed reduced BMD at all sites; 19.1% of patients had osteoporosis. [55]

Poor glycemic control, the presence of diabetic complications, and smoking are also associated with a lower BMD in multiple studies. In a study by Campos Pastor et al, diabetic patients with retinopathy, for example, were much more likely to exhibit osteopenia or osteoporosis. [56] However, the presence of retinopathy and the degree of glycemic control are clearly not independent variables because the mean glycosylated hemoglobin value was significantly higher in the group with retinopathy (8.5% vs 7.1%). BMD also correlates with body mass index, which is dependent upon the degree of insulinization and glycemic control.

Campos Pastor et al observed 62 patients with type 1 diabetes and found that after 7 years of intensive insulin therapy, BMD stabilized at all sites. A significant fall in tartrate-resistant alkaline phosphatase levels (4.3 vs 2.7 IU/L) and a significant rise in intact PTH levels (28 vs 40 ng/L) were also observed. [56]

Addesso et al and Shane et al found that in a type 1 diabetic cohort awaiting SPKT, osteoporosis and osteopenia, respectively, were present in 11% and 21% of patients at the LS spine, 29% and 54% at the femur neck, 25% and 61% at the Ward triangle, and 14% and 64% at the trochanter. [16] Of the 20 patients with available fracture data, 15 (75%) had already sustained a fracture while awaiting transplantation. In total, 12 extremity fractures and 3 rib fractures occurred. The mean age of the patients was 39 years, with a mean duration of type 1 diabetes mellitus of 23 years.

In a Swedish cohort of renal transplant recipients followed by Nisbeth et al, a symptomatic osteoporotic fracture occurred in 40% of the patients with type 1 diabetes but in only 11% of renal transplant recipients without diabetes. [54] Symptomatic bone disease was examined in this cross-sectional study using questionnaires and hospital records in 193 renal transplant recipients with functional grafts 6 months to 23 years after transplantation. Most fractures occurred within the first 3 years posttransplant. Fractures in diabetic patients were often multiple and were located mostly in the appendicular skeleton, ankles, and feet.

A cross-sectional study by Smets et al in 31 Dutch patients at least 12 months following successful SPKT (mean 40 ± 23 mo) found a high prevalence of secondary hyperparathyroidism, increased bone turnover, and fractures. [57] All patients were insulin independent with a mean CrCl level of 64 ± 21 mL/min. Secondary hyperparathyroidism was noted in 55% of patients. Increased osteocalcin, a marker of increased bone turnover, was present in 45%. However, accurate determination of osteocalcin in the SPKT patient is complex, because the clearance of osteocalcin is reduced by a decreased CrCl and osteocalcin levels are raised by hyperglycemia.

In the Smets et al study, osteoporosis (t score < -2.5 standard deviation [SD]) was found in 23% of patients at the lumbar spine, a predominantly trabecular site, but in 58% of patients at the femur neck, a predominantly cortical site. Fractures, which were primarily nonvertebral, were found in 45% of the SPKT patients studied. [57]

Smets and colleagues subsequently prospectively followed 19 consecutive SPKT patients who began taking the synthetic vitamin D analog alfacalcidol (0.25 mcg/d) at the end of the first posttransplantation year, and found a small but significant increase in LS spine BMD in the first 6 months (+1.7 ±2.1%). [57] These patients had, on average, approximately 25 years of type 1 diabetes. None of the patients had osteoporosis at the lumbar spine prior to transplantation, although 7 (37%) had cortical osteoporosis pretransplant.

The authors note that the cumulative prednisone dose was similar in most patients. A significant increase in serum calcium (+0.08 ± 0.02 mmol/L) was noted in the 6 months after alfacalcidol was begun, which was not associated with a significant decrease in PTH, so perhaps the dose was not sufficient to fully normalize PTH secretion. [57]

This paper confirmed a pattern of heightened trabecular and cortical bone loss during the first 6 months after SPKT. In contrast to other studies, [53] however, which suggested continued bone loss up to 18 months postrenal transplant, this study in SPKT recipients suggested stabilization of BMD after the first 6 months posttransplant.

Compared with their baseline, 9 patients (47%) had osteoporosis at the femoral neck, and only 1 patient (5%) developed osteoporosis at the lumbar spine. In this cohort, all fractures occurred more than 1 year posttransplantation; about one third of patients experienced a fracture over a mean follow up period of approximately 3.3 years. [58]

In conclusion, low bone mass is highly prevalent both prior to and following successful SPKT and is associated with a high fracture prevalence. Cortical bone loss is unusually prevalent in this specific transplant population, possibly due to both cortical osteopenia and persistent hyperparathyroidism.


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